Liposome delivery systems have been proposed for a variety of drugs, particularly those which are administered parenterally. Liposomes have the potential of providing a controlled "depot" release of the administered drug over an extended time period, and of reducing toxic side effects of the drug, by limiting the concentration of free drug in the bloodstream. Liposomes can also alter the tissue distribution and uptake of drugs, and the altered tissue distribution, combined with other advantages just mentioned, can significantly increase the therapeutic effectiveness of the drug. Liposome/drug compositions can also increase the convenience of therapy by allowing higher drug dosage and less frequent drug administration. Liposome drug delivery systems are reviewed generally in Poznansky et al.
One group of drugs whose use in liposome delivery systems has been widely studied is the class of anthracene quinones, including, particularly, the anthracycline glycoside antibiotics, exemplified by the anti-tumor drug doxorubicin or "Adriamycin", doxorubicinol, daunorubicin, and daunorubicinol, and their cyanomorpholinyl derivatives. Doxorubicin (DXR) is a potent chemotherapeutic agent effective against a broad spectrum of neoplasms (Aubel-Sadron et al and Young). However, use of the drug in soluble form is limited by serious side effects. Its acute toxicity includes malaise, nausea, vomiting myelosuppression, and severe alopecia. In addition, cumulative and irreversible cardiac damage occurs with repeated administration, which seriously limits the use of the drug in protracted treatment (Young). When administered in liposome form, the drug retains its therapeutic effectiveness against animal tumors, but is significantly less toxic, as judged by reduced mortality (Forssen, Gabizon 1985). The drug-protective effect of liposomes is due, at least in part, to a marked alteration in tissue disposition and drug-release rate of the injected drug (Gabizon 1982; Gabizon 1983; Juliano).
The cardiomyopathy observed in doxorubicin treatment is similar to the cardiac muscle lesions seen in experimental animals under conditions of alpha-tocopherol (.alpha.-T) deficiency (Tomasz), suggesting that the drug-induced lesions are caused by increased free-radical reactions involving membrane lipids. DXR and other anthraquinones, which have the general structure shown in FIG. 1, contain both quinone and hydroquinone groups, and thus might be expected to promote peroxidation reactions involving electron transfer to or from the quinones or hydroquinones. In addition, binding of the drug to lipids through the anthracene moiety would be expected to facilitate lipid involvement in peroxidations reactions. It is known, for example, that DXR binds tightly to cardiolipin, a major lipid component in mitochondria, and enzyme-catalyzed electron transport results in formation of covalent linkages between the drug and lipid (Goormaghtigh).
The free radical mechanism of cardiac toxicity proposed for DXR suggests that a lipophilic free-radical quencher such as vitamin E would be effective in reducing drug toxicity and this, in fact has been found (Myers; Wang; Sonneveld). The referenced studies have shown that vitamin E is effective in reducing cardiotoxicity when administered prior to or concurrent with DXR administration. More recent studies have shown that a liposome drug system with coentrapped DXR and vitamin E is less toxic in animals, and produces less cardiomyopathy, than either vitamin E/DXR or liposome/DXR combinations alone (Olson). The reduced toxicity of liposomes with coentrapped DXR and vitamin E apparently results from a combination of the altered drug distribution and/or lower free drug levels--due to liposomal entrapment of the drug--and from reduced free-radical damage--due to the free-radical quenching activity of vitamin E.
Despite the reduced toxicity of a liposome/DXR/vitamin E formulation, it has been found, in studies conducted in support of the present invention, that the drug and lipids in such formulation can undergo substantial chemical modification, even under anoxic during storage conditions. Such damage increases the toxicity of the drug formulation and appears to compromise the therapeutic action of the drug.